EP2014288A1 - Combinaison de dérivé de benzyl-4, 5-dihydro-1H-imidazole et ligand de récepteur opioïde - Google Patents

Combinaison de dérivé de benzyl-4, 5-dihydro-1H-imidazole et ligand de récepteur opioïde Download PDF

Info

Publication number
EP2014288A1
EP2014288A1 EP07384029A EP07384029A EP2014288A1 EP 2014288 A1 EP2014288 A1 EP 2014288A1 EP 07384029 A EP07384029 A EP 07384029A EP 07384029 A EP07384029 A EP 07384029A EP 2014288 A1 EP2014288 A1 EP 2014288A1
Authority
EP
European Patent Office
Prior art keywords
pain
compound
morphine
xylometazoline
oxymetazoline
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07384029A
Other languages
German (de)
English (en)
Inventor
Luz Romero-Alonso
Rosalía Pascual-Ramón
José Miguel Vela-Hernández
Dr. Helmut H. Buschamnn
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Esteve Pharmaceuticals SA
Original Assignee
Laboratorios del Dr Esteve SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Laboratorios del Dr Esteve SA filed Critical Laboratorios del Dr Esteve SA
Priority to EP07384029A priority Critical patent/EP2014288A1/fr
Priority to PCT/EP2008/005612 priority patent/WO2009007110A2/fr
Publication of EP2014288A1 publication Critical patent/EP2014288A1/fr
Withdrawn legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the present invention refers to a combination of a Compound A, a benzyl-4,5-dihydro-1H-imidazole derivative according to formula (I) and a Compound B, an opioid receptor ligand; especially of xylometazoline or oxymetazoline and a ⁇ -opioid receptor agonist, most preferably of xylometazoline or oxymetazoline and morphine; a medicament comprising this combination; a pharmaceutical formulation for nasal application comprising this combination; or the use of this combination for the treatment of the symptoms of pain, or the prevention or the prophylaxis of the symptoms of pain, whereas pain particularily encompasses visceral pain, chronic pain, cancer pain, acute pain or neuropathic pain, specifically involving also breakthrough pain.
  • PAIN is defined by the International Association for the Study of Pain (IASP) as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage ( IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 210 ). Even though pain is always subjective its causes or syndromes can be classified.
  • IASP International Association for the Study of Pain
  • a long-standing way of treating pain - which is also currently the most common therapeutic approach - is the use of opioids, compounds binding to the receptors of the opioid system ( ⁇ , ⁇ , ⁇ and ORL1).
  • opioids have either been used in clinics or are under investigation with compounds binding to the ⁇ -opioid receptor, like morphine, having currently the highest clinical relevance for the treatment of pain.
  • some of these ⁇ -opioids do show some severe drawbacks, namely dependency/addiction and tolerance. So, for some of these ⁇ -opioids persons having been exposed for an extended time to compounds like morphine - especially in higher dosages - did show signs of addiction from continuous exposure.
  • the analgesic effect of the treatment severely declined, which is a dramatic situation for these patients given the circumstances of their suffering.
  • BTP breakthrough pain
  • persistent pain lasting 12 or more hours/day
  • breakthrough pain BTP
  • BTP breakthrough pain
  • ATC around-the-clock
  • the main object of this invention is a combination of compounds comprising
  • the compound B may be in neutral form, the form of a base or acid, in the form of a salt, preferably a physiologically acceptable salt, in the form of a solvate or of a polymorph and/or in the form of in the form of its racemate, pure stereoisomers, especially enantiomers or diastereomers or in the form of mixtures of stereoisomers, especially enantiomers or diastereomers, in any suitable ratio.
  • Treating” or “treatment” as used in this application are defined as including the treatment of the symptoms of pain, as well as treatment of the disease or disease consequences causing the symptoms, the prevention or the prophylaxis of the symptoms of pain, as well as the prevention or the prophylaxis of the disease or disease consequences causing the symptoms.
  • Preferably “treating” or “treatment” as used in this application are defined as including the treatment of the symptoms of pain, as well as treatment of the disease consequences causing the symptoms, the prevention or the prophylaxis of the symptoms of pain, as well as the prevention or the prophylaxis of the disease consequences causing the symptoms.
  • Most preferably “treating” or “treatment” as used in this application are defined as including the treatment of the symptoms of pain, and the prevention or the prophylaxis of the symptoms of pain.
  • Compound binding to an opioid receptor as used in this application is/are defined as having a K i Value in their binding to at least one of the various opioid-receptor of ⁇ 1 ⁇ M.
  • Compound binding to the ⁇ -opioid receptor as used in this application is/are defined as having a K i Value in their binding to the ⁇ -opioid-receptor ⁇ 1 ⁇ M.
  • Assays that may be used for determining the affinity and selectivity of a compound binding to the ⁇ -opioid receptor especially a ⁇ -receptor agonist are well known in the art and especially measuring the affinities to these receptors are offered by a number of well-known service companies.
  • a complete comprehensive list of compounds binding to opioid receptors, especially to the ⁇ -opioid receptor, together with their Ki-values for different opioid receptors are given in H.Buschmann et al, Handbook of Pain, (2002), Wiley , and is hereby incorporated by reference and forms part of the disclosure.
  • solvate is to be understood as meaning any form of a compound in the invention in which this compound has attached to it via non-covalent binding another molecule (most likely a polar solvent) especially including hydrates and alcoholates, e.g. methanolate.
  • salt is to be understood as meaning any form of compound A or compound B according to the invention in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution.
  • a counter-ion a cation or anion
  • complexes of the active compound with other molecules and ions in particular complexes which are complexed via ionic interactions.
  • physiologically acceptable salt also means in the context of this invention any salt that is physiologically tolerated (most of the time meaning not being toxic- especially not caused by the counter-ion) if used appropriately for a treatment especially if used on or applied to humans and/or mammals.
  • physiologically acceptable salts can also be formed with anions or acids in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention - usually protonated, for example on the nitrogen - as the cation with at least one anion which are physiologically tolerated - especially if used on humans and/or mammals.
  • the salt formed with a physiologically tolerated acid that is to say salts of the particular active compound with inorganic or organic acids which are physiologically tolerated - especially if used on humans and/or mammals.
  • physiologically tolerated salts of particular acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, gluconic acid or citric acid.
  • physiologically acceptable salts can be formed with cations or bases and in the context of this invention is understood as meaning salts of at least one of the compounds used according to the invention - usually a (deprotonated) acid - as an anion with at least one, preferably inorganic, cation which is physiologically tolerated - especially if used on humans and/or mammals.
  • the salts of the alkali metals and alkaline earth metals are particularly preferred, and also those with NH4, but in particular (mono)- or (di)sodium, (mono)- or (di)potassium, magnesium or calcium salts.
  • the compound A or compound B of the invention may be in crystalline form or either as free compounds or as solvates and it is intended that those forms are within the scope of the present invention.
  • Methods of solvation are generally known within the art. Suitable solvates are pharmaceutically acceptable solvates.
  • the term "solvate" according to this invention is to be understood as meaning any form of the active compound according to the invention in which this compound has attached to it via non-covalent binding another molecule (most likely a polar solvent) especially including hydrates and alcoholates, e.g. methanolate.
  • the compound A or compound B of the invention may also be in form of a polymorph.
  • the compounds in the combination of the invention are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon or 15 N-enriched nitrogen are within the scope of this invention.
  • the compound A is either xylometazoline or oxymetazoline or combination thereof; in neutral form, in the form of a base, or in the form of a salt, preferably a physiologically acceptable salt, or in the form of a solvate or as a polymorph.
  • xylometazoline or oxymetazoline are either in form of the free base or in the form of the hydrochloride.
  • Xylometazoline is a topical decongestant usually used in the form of xylometazoline hydrochloride in nasal sprays or drops. It is a well-known compound with sympathomimetic properties acting on alpha adrenergic receptors used in nasal sprays for years. Processes for its production are well known in the art. It has the following structure:
  • Oxymetazoline is a topical decongestant usually used in the form of oxymetazoline hydrochloride in nasal sprays or drops. It is a well-known compound with sympathomimetic properties acting on alpha adrenergic receptors used in nasal sprays for years. Processes for its production are well known in the art. It has the following structure:
  • Another especially preferred embodiment of the invention encompasses combinations according to the invention, wherein the compound B is acting as an agonist, preferably a full or a partial agonist or mixed agonist/antagonist on an opioid receptor, preferably on the ⁇ -opioid receptor.
  • An "Agonist” is defined as a compound that binds to a receptor and has an intrinsic effect, and thus, increases the basal activity of a receptor when it contacts the receptor.
  • Full agonists show the maximum effect on the receptor, whereas a partial agonist is giving less (e.g. 80%) of the response of the full agonist as a maximum.
  • Included in this definition are also compounds acting as mixed agonists/antagonists on the receptor, thus showing agonistic and also antagonistic activity.
  • a highly preferred embodiment of the invention encompasses combinations according to the invention, wherein
  • the compound B binding to an opioid receptor is binding to an opioid receptor, preferably the ⁇ -opioid receptor, with a Ki-value lower than 1000 nM, preferably lower than 200 nM, more preferably lower than 100 nM, even more preferably lower than 50 nM.
  • the compound B binding to an opioid receptor is binding to an opioid receptor, preferably to the ⁇ opioid receptor, with a Ki-value lower than 1000 nM, preferably lower than 200 nM, more preferably lower than 100 nM, even more preferably lower than 50 nM, highly preferably lower than 10 nM.
  • the compound B binding to the ⁇ -opioid receptor is selected from
  • the compound B binding to the ⁇ -opioid receptor is selected from
  • a highly preferred embodiment of the current invention is a combination according to the invention, wherein the compound A is selected from
  • the compounds of group A or B or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form.
  • pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • Purity levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%. In a preferred embodiment it is above 95% of the compound of formula (I) or, or of its salts, solvates or prodrugs.
  • the combination according to the invention is not toxic.
  • a further aspect of the invention refers to a medicament comprising a combination according to the invention, and optionally one or more pharmaceutically acceptable adjuvants.
  • the dose administered can be quite low depending on the route of administration.
  • an effective administered amount of the combination of the invention will depend on the relative efficacy of the combination chosen, the severity of the disorder being treated and the weight of the sufferer.
  • active compounds will typically be administered once or more times a day for example 1, 2, 3 or 4 times daily, with typical total daily doses in the range of from 0.1 to 1000 mg/kg/day.
  • Any medicament according to the invention contains the active ingredient/combination as well as optionally at least one auxiliary material and/or additive and/or optionally another active ingredient.
  • the auxiliary material and/or additive can be specifically selected from conserving agents, emulsifiers and/or carriers for parenteral application.
  • the selection of these auxiliary materials and/or additives and of the amounts to be used depends upon how the pharmaceutical composition is to be applied. Examples include here especially parenteral like intravenous subcutaneous or intramuscular application formulations but which could also be used for other administration routes.
  • Suitable forms of the pharmaceutical formulation or medicament according to the invention include tablets, sachets, capsules, sprays, gels; solutions or dispersions for injection, inhalation, spraying or ingestion; suppositories, patches, films, lolli-pops, chewing gums etc.
  • Routes of administration can include intramuscular injection, intraveneous injection, subcutaneous injection, sublingual, intranasal, bucal, patch through skin, oral ingestion, implantable osmotic pump, collagen implants, aerosols or suppository.
  • Another highly preferred aspect of the invention is relating to a pharmaceutical formulation for nasal application comprising a combination according to the invention, and one or more pharmaceutically acceptable adjuvants.
  • the combination of compounds according to the invention do show a further surprisingly high potential knowing that with examples of Compound B like morphine having been tested successfully in clinics ( Illum et al, JPET, 3001, (1), 391- 400, (2002 ); Pavis et al., J. of Pain and Symptom Management, 24 (6), 598 - 602 (2002 )) and knowing that the most prominent examples of compound A, xylometazoline or oxymetazoline or their respective hydrochlorides, are used for decades in nasal sprays or drops.
  • the pharmaceutical formulation is either in form of a solution, in form of a dispersion, in form of a gas, in form of a gel or in form of a powder, preferably in form of a solution, in form of a dispersion, or in form of a powder.
  • the pharmaceutical formulation for nasal application according to the invention is comprising at least one pharmaceutically acceptable adjuvants, selected from
  • micospheres and nanoparticles may be used in the pharmaceutical formulations-preferably for nasal application - according to the invention.
  • the pharmaceutical formulation is comprising 30.0 to 0.5 mg/ml of xylometazoline hydrochloride, or 50.0 to 0.5 mg/ml of oxymetazoline hydrochloride, or 30.0 to 0.5 mg/ml of the benzyl-4,5-dihydro-1H-imidazole derivative according to formula (I), preferably xylometazoline or oxymetazoline or their physiologically acceptable salts, especially their hydrochloride salt, solvates or polymorphs.
  • the pharmaceutical formulation is comprising 400 to 1 mg/ml or preferably 200 to 5 mg/ml of compound B, preferably of buprenorphine, fentanyl, sufentanil, carfentanil, lofentanil, alfentanil, ohmefentanil, remifentanil, oxycodone, butorphanol, morphine-6-glucoronide, or morphine, most preferably of morphine as free base, physiologically acceptable salt, especially the hydrochloride, gluconate or sulfate salt, or as solvate.
  • compound B preferably of buprenorphine, fentanyl, sufentanil, carfentanil, lofentanil, alfentanil, ohmefentanil, remifentanil, oxycodone, butorphanol, morphine-6-glucoronide, or morphine, most preferably of morphine as free base, physiological
  • the pharmaceutical formulation is comprising a combination according to the invention in a weight per weight ratio of compound A to compound B of 25 to 1 to 0.1 to 1.
  • Another aspect of the invention is a use of at least one combination according to the invention or of xylometazoline or oxymetazoline or their physiologically acceptable salts, solvates or polymorphs for the manufacture of a medicament for the treatment of pain, preferably visceral pain, chronic pain, cancer pain, acute pain, breaktrough pain or neuropathic pain, allodynia or hyperalgesia.
  • Another aspect of the invention is a use of at least one combination according to the invention for the manufacture of a medicament for the treatment of pain, preferably visceral pain, chronic pain, cancer pain, acute pain, breaktrough pain or neuropathic pain, allodynia or hyperalgesia.
  • Another aspect of the invention is a use of xylometazoline or oxymetazoline or their physiologically acceptable salts, solvates or polymorphs for the manufacture of a medicament for the treatment of pain, preferably visceral pain, chronic pain, cancer pain, acute pain, breaktrough pain or neuropathic pain, allodynia or hyperalgesia.
  • the medicament is used for the treatment of pain in which the stimulus evoking the pain is thermal.
  • the medicament is used for the treatment of neuropathic pain - or its subgroups - in which the stimulus evoking the neuropathic pain is thermal.
  • the medicament is used for the treatment of pain in which the stimulus evoking the pain is mechanical.
  • the medicament is used for the treatment of neuropathic pain - or its subgroups - in which the stimulus evoking the neuropathic pain is mechanical.
  • Some known subgroups of pain are acute pain, chronic pain, visceral pain and including also headaches, especially migraine.
  • Other subgroups of pain are neuropathic pain, hyperalgesia and allodynia.
  • Neuroneuropathic pain is defined by the IASP as “pain initiated or caused by a primary lesion or dysfunction in the nervous system” ( IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 210 ).
  • Neuroogenic Pain is defined by the IASP as “pain initiated or caused by a primary lesion, dysfunction or transitory perturbation in the peripheral or central nervous system”.
  • diabetes especially diabetes II.
  • IASP allodynia
  • hypoalgesia is defined as "an increased response to a stimulus which is normally painful( IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 211 ).
  • the neuropathic pain is selected from central pain, hyperpathia, peripheral neuropathic pain or peripheral neurogenic pain, causalgia, hyperesthesia, neuralgia, neuritis, or neuropathy.
  • central pain is defined as "a pain initiated or caused by a primary lesion or dysfunction in the central nervous system” ( IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 211 ).
  • Causalgia is defined as "a syndrome of sustained burning pain, allodynia and hyperpathia after a traumatic nerve lesion, often combined with vasomotor and sudomotor dysfunction and later trophic changes" ( IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 210 ).
  • hypoesthesia is defined as "increased sensitivity to stimulation, excluding the senses” ( IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 211 ).
  • nervegia is defined as "Pain in the distribution of a nerve or nerves” ( IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 212 ).
  • nerves are defined as “Inflammation of a nerve or nerves” ( IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 212 ).
  • neuroneuropathy is defined as "a disturbance of function or pathological change in a nerve: in one nerve mononeuropathy, in several nerves mononeuropthy multiplex, if diffuse and bilateral, polyneuropathy” ( IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 212 ).
  • hypopathia is defined as "a painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold" ( IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 212 ).
  • the IASP draws the following difference between "allodynia”, “hyperalgesia” and “hyperpathia” ( IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 212 ): Allodynia Lowered threshold Stimulus and response mode differ Hyperalgesia Increased response Stimulus and response rate are the same Hyperpathia Raised threshold; Increased response Stimulus and response rate may be the same or different
  • Another aspect of the ionvention refers to the use of at least one combination according to the invention for the manufacture of a medicament for the treatment of sleep disorder, shift worker syndrome, jet lag, depression, seasonal affective disorder, migraine, anxiety, psychosis, schizophrenia, cognition and memory disorders, neuronal degeneration resulting from ischemic events, cardiovascular diseases such as hypertension, irritable bowel syndrome, inflammatory bowel disease, spastic colon or urinary incontinence.
  • Included in this invention as a very preferred aspect is especially also a method of treatment of a patient or a mammal, including men, suffering from pain by applying to the patient or mammal either a suitable amount of the combination according to the invention comprising at least one compound A and at least one compound B or by applying to the patient or mammal first a suitable amount of compound A followed by applying to the patient or mammal a suitable amount of compound B or by applying to the patient or mammal first a suitable amount of compound B followed by applying to the patient or mammal a suitable amount of compound A.
  • the patient suffering from pain is suffering from visceral pain, chronic pain, cancer pain, acute pain, breaktrough pain or neuropathic pain, allodynia or hyperalgesia, or more preferably from chronic pain, or cancer pain, and/or from breaktrough pain.
  • a suitable amount of the combination according to the invention comprising at least one compound A and at least one compound B is applied to the patient in need thereof in form of a pharmaceutical formulation or medicament, optionally followed by either one or more further applications of a suitable amount of the combination according to the invention comprising at least one compound A and at least one compound B, and/or one or more further applications of a suitable amount of compound A and/or compound B.
  • a suitable amount of compound A is applied to the patient in need thereof, followed - optionally even simultaneously - by application of a suitable amount of compound B, optionally followed by either one or more further applications of a suitable amount of the combination according to the invention comprising at least one compound A and at least one compound B, and/or one or more further applications of a suitable amount of compound A and/or compound B.
  • a suitable amount of compound B is applied to the patient in need thereof, followed - optionally even simultaneously - by application of a suitable amount of compound A, optionally followed by either one or more further applications of a suitable amount of the combination according to the invention comprising at least one compound A and at least one compound B, and/or one or more further applications of a suitable amount of compound A and/or compound B.
  • the pharmaceutical formulations or medicaments applied may be prepared to be suitable for intramuscular injection, intraveneous injection, subcutaneous injection oral ingestion, sublingual, intranasal, or bucal application, in form of a patch through skin, an implantable osmotic pump, collagen implants, aerosols or of a suppository.
  • the pharmaceutical formulations or medicaments applied are suitable for nasal application, sublingual application, oral ingestion or for injection, in highly preferred embodiment suitable for nasal application.
  • the pharmaceutical formulations or medicaments are in the form of a solution, in form of a dispersion, in form of a gas, in form of a gel or in form of a powder, preferably in form of a solution, in form of a dispersion, or in form of a powder.
  • the pharmaceutical formulations or medicaments are comprising 30.0 to 0.5 mg/ml of xylometazoline hydrochloride, or 50.0 to 0.5 mg/ml of oxymetazoline hydrochloride or are comprising 30.0 to 0.5 mg/ml of the benzyl-4,5-dihydro-1H-imidazole derivative according to formula (I), preferably xylometazoline or oxymetazoline or their physiologically acceptable salts, especially their hydrochloride salt, solvates or polymorphs.
  • the pharmaceutical formulations or medicaments are comprising 400 to 1 mg/ml or preferably 200 to 5 mg/ml of compound B, preferably of buprenorphine, fentanyl, sufentanil, carfentanil, lofentanil, alfentanil, ohmefentanil, remifentanil, oxycodone, butorphanol, morphine-6-glucoronide, or morphine, most preferably of morphine as free base, physiologically acceptable salt, especially the hydrochloride, gluconate or sulfate salt, or as solvate.
  • compound B preferably of buprenorphine, fentanyl, sufentanil, carfentanil, lofentanil, alfentanil, ohmefentanil, remifentanil, oxycodone, butorphanol, morphine-6-glucoronide, or morphine, most preferably of morphine as
  • the pharmaceutical formulations or medicaments are comprising a combination according to the invention in a marh per weight ratio of compound A to compound B of 25 to 1 to 0.1 to 1.
  • mice Male CD1 mice aged from 6 to 8 weeks old are used in these studies. Animals are housed in groups of five, provided with food and water ad libitum and kept in controlled laboratory conditions with the temperature maintained at 21 ⁇ 1 °C and light in 12 h cycles (on at 07:00 h and off at 19:00 h). Experiments are carried out in a soundproof and air-regulated experimental room. The number of mice ranges from 8 to 16 per group in each individual experiment.
  • Drugs used for treatments are: Morphine and Xylometazoline as well as Oxymetazoline. Doses are calculated based on the molecular weight of the free base or of the respective salts, where applicable.
  • analgesic activity of the inventive active substance combination is determined in male CDR1 following and adapting the description in the publication of G. Woolfe and A. D. MacDonald, J. Pharm. Exp. Ther. 1944, 80, pages 300-307 .
  • the respective description of this publication is incorporated by reference and forms part of the present disclosure.
  • mice are put onto a plate, which is heated to 50 °C and the time is determined until the mice showed signs of pain such as vigorous and repeated licking of the hind or front paws, jumping or pulling back the paws.
  • the mice are kept on the hot plate for no longer than 40 seconds in order to avoid the development of cutaneous lesions.
  • the vehicle, the active substances and the inventive active substance combination to be tested are administered - sometimes in differing concentrations - either by s.c. or by i.p. injection to different groups of mice.
  • the analgesic efficacy of the active substances or active substance combination is calculated on the basis of the values obtained for the comparison group of mice to which is only administered the vehicle (baseline). By comparing to baseline (defined as 0% analgesia) and to a failure of pain signs (defined as 100% analgesia) Percentage of analgesia is determined. In some cases based on this calculation and with different concentrations of the active substances or active substance combination ED50 values are determined.
  • the test was performed as previously described ( Moncada et al. (2003), Eur. J. Pharmacol. 465, 53-60 ). Briefly, the animals (male CD1 mice) were restrained in a Plexiglas tube and placed on the tail flick apparatus (LI 7100, Letica, S.A., Spain). A noxious beam of light was focussed on the tail about 4 cm from the tip, and the tail flick latency was recorded automatically to the nearest 0.1 s. The intensity of the radiant heat source was adjusted to yield baseline latencies between 3 and 5 s; this intensity was never changed and any animal whose baseline latency was outside the pre-established limits was excluded from the experiments. In order to minimise injury in the animals, a cut-off time of 10 s was used.
  • Figure 1 refers to Example 1), a Tail-Flick-Test.
  • Male CD1 Mice were receiving s.c. injections of 2mg/kg morphine and i.p. injections of 5mg/kg of xylometazoline and oxymetazoline 45 min before measurement.
  • the Baseline was determined based on saline injection.
  • Tail-Flick-Test (Combination of Morphine + Xylometazoline and Oxymetazoline):
  • mice were placed 45 minutes after injection in the tail-flick apparatus.
  • the Baseline was determined based on saline injection. Significance values are determined vs. the saline group and vs. the respective morphine group.
  • mice are placed 30 minutes after injection on the hot plate heated to 50° C.
  • the signs of pain shown are divided by Front Paw Licking (FPL), Hind Paw Licking (HPL) and Jumping and measured/counted.
  • the Baseline is determined based on saline injection. Significance values are determined vs. the saline group and vs. the respective morphine group.
  • mice are placed 30 minutes after injection on the hot plate heated to 50° C.
  • the signs of pain shown are divided by Front Paw Licking (FPL), Hind Paw Licking (HPL) and Jumping and measured/counted.
  • the Baseline is determined based on saline injection. Significance values are determined vs. the saline group and vs. the respective morphine group.
  • mice Male CD1 Mice are devided in 2 groups, the group receiving s.c. injections of morphine in high doses to develop tolerance (hereinafter called “Tolerants”), and the group receiving only vehicle (callede “Non-Tolerants”).
  • Tolerants the group receiving s.c. injections of morphine in high doses to develop tolerance
  • Non-Tolerants the group receiving only vehicle
  • the following treatment scheme was followed: Tolerance induction Day 1 Day 2 Day 3 Day 4 Morphine (mg/kg sc) Morning 30 60 120 Afernoon 30 45 90 120 Vehicle Vehicle Vehicle Morning Afernoon Vehicle Vehicle Vehicle Vehicle Vehicle Vehicle Vehicle
  • Tolerants group is expressing tolerance towards morphine. Both groups Tolerants and Non-Tolerants are tested on day 5.
  • mice are placed 30 minutes after injection on the hot plate heated to 50° C.
  • the signs of pain shown are divided by Front Paw Licking (FPL), Hind Paw Licking (HPL) and Jumping and measured/counted.
  • FPL Front Paw Licking
  • HPL Hind Paw Licking
  • Jumping and measured/counted.
  • the Baseline is determined based on saline injection. Significance values are determined.
  • mice Male CD1 Mice are devided in 2 groups, the group receiving s.c. injections of morphine in high doses to develop tolerance (hereinafter called “Tolerants”), and the group receiving only vehicle (called “Non-Tolerants”).
  • Tolerants the group receiving s.c. injections of morphine in high doses to develop tolerance
  • Non-Tolerants the group receiving only vehicle
  • Tolerants group is expressing tolerance towards morphine. Both groups, Tolerants and Non-Tolerants, are tested on day 5.
  • mice are placed 45 minutes after injection in the tail-flick apparatus.
  • the Baseline is determined based on saline injection. Significance values are determined.

Landscapes

  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Otolaryngology (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Pain & Pain Management (AREA)
  • Emergency Medicine (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP07384029A 2007-07-10 2007-07-10 Combinaison de dérivé de benzyl-4, 5-dihydro-1H-imidazole et ligand de récepteur opioïde Withdrawn EP2014288A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP07384029A EP2014288A1 (fr) 2007-07-10 2007-07-10 Combinaison de dérivé de benzyl-4, 5-dihydro-1H-imidazole et ligand de récepteur opioïde
PCT/EP2008/005612 WO2009007110A2 (fr) 2007-07-10 2008-07-09 Combinaison de dérivé de benzyl-4,5-dihydro-1h-imidazole et d'un ligand du récepteur opioïde

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP07384029A EP2014288A1 (fr) 2007-07-10 2007-07-10 Combinaison de dérivé de benzyl-4, 5-dihydro-1H-imidazole et ligand de récepteur opioïde

Publications (1)

Publication Number Publication Date
EP2014288A1 true EP2014288A1 (fr) 2009-01-14

Family

ID=38519694

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07384029A Withdrawn EP2014288A1 (fr) 2007-07-10 2007-07-10 Combinaison de dérivé de benzyl-4, 5-dihydro-1H-imidazole et ligand de récepteur opioïde

Country Status (2)

Country Link
EP (1) EP2014288A1 (fr)
WO (1) WO2009007110A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140051738A1 (en) * 2011-04-26 2014-02-20 Nir Barak Oxymetazoline For The Treatment Of Ano-Rectal Disorders

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102010008670A1 (de) 2010-02-19 2011-08-25 Bayerische Motoren Werke Aktiengesellschaft, 80809 Geberarmatur
SI2588093T1 (sl) 2010-06-30 2016-10-28 Gruenenthal Gmbh Tapentadol za uporabo pri zdravljenju sindroma razdražljivega črevesja
CN111606816A (zh) 2017-05-22 2020-09-01 扬子江药业集团有限公司 一种地佐辛晶型及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002026223A2 (fr) * 2000-09-29 2002-04-04 Board Of Trustees Operating Michigan State University Preparations pharmaceutiques de catecholamine et procedes
WO2005097192A2 (fr) * 2004-04-05 2005-10-20 Laboratorios Del Dr. Esteve, S.A. Combinaison de substances actives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002026223A2 (fr) * 2000-09-29 2002-04-04 Board Of Trustees Operating Michigan State University Preparations pharmaceutiques de catecholamine et procedes
WO2005097192A2 (fr) * 2004-04-05 2005-10-20 Laboratorios Del Dr. Esteve, S.A. Combinaison de substances actives

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BENTLEY G A ÄREPRINT AUTHORÜ ET AL: "THE ANTI NOCICEPTIVE ACTION OF ALPHA AGONIST DRUGS AND THEIR INTERACTIONS WITH OPIOID MECHANISMS", BRITISH JOURNAL OF PHARMACOLOGY, BASINGSTOKE, HANTS, GB, vol. 79, no. 1, 1983, pages 125 - 134, XP009089978, ISSN: 0007-1188 *
SHERMAN S E ET AL: "Intrathecal oxymetazoline produces analgesia via spinal alpha-adrenoceptors and potentiates spinal morphine", EUROPEAN JOURNAL OF PHARMACOLOGY, AMSTERDAM, NL, vol. 148, no. 3, 13 April 1988 (1988-04-13), pages 371 - 380, XP009089985, ISSN: 0014-2999 *
SHYU, W.C. ET AL.: "The absolute bioavailability of transnasal butorphanol in patients experiencing rhinitis", EUR J CLIN PHARMACOL, vol. 45, 1993, pages 559 - 562, XP009089983 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140051738A1 (en) * 2011-04-26 2014-02-20 Nir Barak Oxymetazoline For The Treatment Of Ano-Rectal Disorders
AU2012247125B2 (en) * 2011-04-26 2017-03-09 Rdd Pharma Ltd. Oxymetazoline for the treatment of ano-rectal disorders

Also Published As

Publication number Publication date
WO2009007110A2 (fr) 2009-01-15
WO2009007110A3 (fr) 2009-04-02

Similar Documents

Publication Publication Date Title
US9744174B2 (en) Method for noribogaine treatment in patients on methadone
US10952976B2 (en) Compositions and methods for treating respiratory depression with fenfluramine
AU758448B2 (en) Topical compositions comprising an opioid analgesic and an NMDA antagonist
JP2002506047A (ja) Ｎｍｄａレセプター拮抗薬及び麻酔性鎮痛薬を含む鎮痛組成物。
NZ568313A (en) Pharmaceutical compositions comprising buprenorphine
JP2003535833A (ja) ナルブフィンとオピオイドアンタゴニストを使用した疼痛の処置法
JP5867081B2 (ja) 胆道疾患の治療又は予防剤
JP2011515485A (ja) ロフェキシジンを経粘膜送達するための組成物およびその方法
US20230090174A1 (en) Novel methods
CH708257B1 (de) Zusammensetzung zur Behandlung einer Opioid-induzierten unerwünschten pharmakodynamischen Reaktion.
EP2014288A1 (fr) Combinaison de dérivé de benzyl-4, 5-dihydro-1H-imidazole et ligand de récepteur opioïde
US20030130314A1 (en) Analgesic delivery systems and methods of use
EP2151240A1 (fr) Agent thérapeutique ou prophylactique de la dyskinésie
US20060110333A1 (en) Composition for nasal absorption
US10874658B2 (en) Sublingual opioid formulations containing naloxone
JP5343848B2 (ja) 統合失調症の治療または予防剤
EP1702627A1 (fr) Combinaison analgésique comprenant des inhibiteurs de canaux sodiques et des antagonistes d'opioïdes
ES2350439B1 (es) Combinacion de un derivado del bencil-4,5-dihidro 1h-imidazol y un receptor opioide.
US20100048605A1 (en) Synergistic effects of combinations of nornicotine and opioids for the treatment of pain
US20150352099A1 (en) Compositions and Methods of Reducing Sedation
Lerche Opioid Agonists and Antagonists
WO2022119862A1 (fr) Traitement de la douleur et de problèmes neurologiques
WO2024073628A1 (fr) Mélanges d'inversion de surdose d'opioïdes
JP2002308769A (ja) 止痒剤
KR20140106720A (ko) 만성 통증 완화에 이용되는 점막 관통 약물 전달 장치

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK RS

AKX Designation fees paid
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20090715

REG Reference to a national code

Ref country code: DE

Ref legal event code: 8566